API

Relationship: 868

Title

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Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen

Upstream event

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Induction, CYP1A2/CYP1A5

Downstream event

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Oxidation, Uroporphyrinogen

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
Aryl hydrocarbon receptor activation leading to uroporphyria directly leads to Moderate Weak

Taxonomic Applicability

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Term Scientific Term Evidence Link
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Strong NCBI
human Homo sapiens Strong NCBI
chicken Gallus gallus Strong NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Life Stage Applicability

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Term Evidence
Adults Strong
Juvenile Strong

How Does This Key Event Relationship Work

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The oxidation of uroporphorynogen to its corresponding porphyrin (UROX) is preferentially catalyzed by the phase one metabolizing enzyme, CYP1A2, in mammals[1][2] and CYP1A5 in birds[3]. Uroporphyrinogen, an intermediate in heme biosynthesis, is normally converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD)[4]; induction of CYP1A2 expression translates to increased protein levels and therfore an increased incidence of binding, and oxidation of uroporphyrinogen, preventing its normally dominant conversion to coproporphyrinogen.

Weight of Evidence

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WOE for this KER is moderate.

Biological Plausibility

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Uroporphyrinogen has clearly been identified as a substrate of CYP1A2/5, which results in its oxidation to uroporphyrin[1][2][3].

Empirical Support for Linkage

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Include consideration of temporal concordance here

UROX activity is increased by inducers of the CYP1A subfamily[4][1] and inhibited by substrates of CYP1A2[2], indicating that uroporphorynogen binds to the active site of CYP1A2. Furthermore, mice with a higher endogenous level of CYP1A2 are more susceptible to porphyrin accumulation[5] and CYP1A2 knock-out prevents chemical-induced uroporphyria all-together[6][7][8]; therefore, CYP1A2 is essential for UROX. A mild porphyric response was observed in the presence of iron loading and 5-aminolevulinic acid (ALA; a heme precursor) in AHR-/- mice, indicating that CYP1A2 induction is not absolutely necessary, but that constitutive CYP1A2 levels are sufficient for UROX under certain conditions[9].

Uncertainties or Inconsistencies

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Although CYP1A2 plays an essential role in UROX in animal models of porphyria, it seems to be less significant in human development of porphyria cutanea tarda. UROX activity in human liver microsomes was not correlated with CYP1A2 content. Experiments with different expression systems confirmed that human CYP1A2 catalyzes UROX, but with a lower specific activity than that of the mouse orthologue[10].

It is also worth noting that there exists a secondary, CYP1A2-independent pathway to UROX that is hypothesized to depend solely on iron. Phillips et al.[11] were able to generate uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+) to develop porphyria in the absence of external stimuli; CYP1A2 knockout alone prevented porphyrin accumulation, but with the addition of iron and ALA to the triple knockout, modest porphyria was observed. Therefore, under extreme porphyric conditions, UROX can occure in the absence of the CYP1A2 enzyme.

Quantitative Understanding of the Linkage

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Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Correlation between total hepatic uroporphyrin accumulation and hepatic CYP1A2 activities in mice after exposure to TCDD (A), 4-PeCDF (B), PCB 126 (C), or PCB 118 (D). (Source: van Birgelen et al. (1996). Toxicol. Appl. Pharmacol. 138 (1), 98-109.)

UROX is positively correlated with CYP1A2/5 activity[12] but this relationship has not been quantitatively describes. It has been noted however, that a CYP1A2 induction of just 2-fold dramatically induces porphyrin accumulation in iron-loaded mice[5].

Evidence Supporting Taxonomic Applicability

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CYP1A2 catalyzes UROX in mice, rats and humans[1][2][11], as does CYP1A5 in chickens[3], but may not be essential for UROX in humans[11].

References

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  1. 1.0 1.1 1.2 1.3 Jacobs, J. M., Sinclair, P. R., Bement, W. J., Lambrecht, R. W., Sinclair, J. F., and Goldstein, J. A. (1989). Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem. J 258 (1), 247-253.
  2. 2.0 2.1 2.2 2.3 Lambrecht, R. W., Sinclair, P. R., Gorman, N., and Sinclair, J. F. (1992). Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch. Biochem. Biophys. 294 (2), 504-510.
  3. 3.0 3.1 3.2 Sinclair, P. R., Gorman, N., Walton, H. S., Sinclair, J. F., Lee, C. A., and Rifkind, A. B. (1997). Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab. Dispos. 25 (7), 779-783.
  4. 4.0 4.1 Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
  5. 5.0 5.1 Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002). Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35 (4), 912-921.
  6. Greaves, P., Clothier, B., Davies, R., Higginson, F. M., Edwards, R. E., Dalton, T. P., Nebert, D. W., and Smith, A. G. (2005) Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse. Biochem. Biophys. Res. Commun. 331 (1), 147-152.
  7. Sinclair, P. R., Gorman, N., Dalton, T., Walton, H. S., Bement, W. J., Sinclair, J. F., Smith, A. G., and Nebert, D. W. (1998) Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Biochem. J. 330 ( Pt 1), 149-153.
  8. Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001) Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173 (2), 89-98.
  9. Davies, R., Clothier, B., Robinson, S. W., Edwards, R. E., Greaves, P., Luo, J., Gant, T. W., Chernova, T., and Smith, A. G. (2008) Essential role of the AH receptor in the dysfunction of heme metabolism induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chem. Res. Toxicol. 21 (2), 330-340.
  10. Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S., and Sinclair, J. F. (1998b). Uroporphyrinogen oxidation catalyzed by human cytochromes P450. Drug Metab Dispos. 26 (10), 1019-1025.
  11. 11.0 11.1 11.2 Phillips, J. D., Kushner, J. P., Bergonia, H. A., and Franklin, M. R. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol. Dis. 47 (4), 249-254.
  12. van Birgelen, A. P., DeVito, M. J., Akins, J. M., Ross, D. G., Diliberto, J. J., and Birnbaum, L. S. (1996). Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls derived from hepatic porphyrin accumulation in mice. Toxicol. Appl. Pharmacol. 138 (1), 98-109.